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NIHR Signal Early use of tranexamic acid reduces bleeding more effectively

In people bleeding after trauma or giving birth, tranexamic acid within an hour of the start of bleeding increases the chances of survival by 72% compared with a placebo. Overall the trial data showed that at least six deaths from bleeding complications were prevented for every 1,000 people treated and potentially more if treatment is started early.

Tranexamic acid is an antifibrinolytic drug which reduces the breakdown of blood clots and is known to reduce serious bleeding. The researchers wanted to see if the benefits of tranexamic acid were greater if given as early as possible.

The current guidance recommends giving tranexamic acid for bleeding after trauma and in women with bleeding after giving birth. It is now clearer that every 15-minute delay after the first hour can reduce survival by about 10%.

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Why was this study needed?

In the UK over 16,000 people per year suffer major trauma, and it is the leading cause of death in those under 40 years old. Uncontrolled bleeding is a major contributor to death, and the estimated annual cost to the NHS of treating severe bleeding after trauma is over £148 million.

Between 2013 and 2015, 10 women in the UK died from bleeding after giving birth.

Evidence shows that tranexamic acid may reduce the risk of death in people with bleeding after trauma and in women who bleed after giving birth.

It is not yet clear to what extent this risk changes depending on treatment delay. The researchers wanted to find out what the evidence said about time to administration of tranexamic acid treatment in two clinical settings and to what extent delay beyond an hour affected survival.

What did this study do?

This meta-analysis included two randomised controlled trials involving 40,138 people with bleeding who received tranexamic acid or a placebo.

One trial (CRASH-2) included people with bleeding after trauma. The second (WOMAN) included women with bleeding after giving birth.

The researchers looked at the survival rates in active and placebo arms of these trials and analysed the link between this and the timing of tranexamic acid administration. It is not clear from the review what dose was given in each trial.

These trials were large and with over 40,000 patients recruited between them provide a precise estimate of this effect. Both trials included patients from developed and less-developed countries. The timing of original trauma in CRASH-2 was not always certain and so treatment delay time could have been underestimated but is unlikely to have changed the overall pattern of these findings.

What did it find?

A total of 3,558 people died, and 40% (1,408) died due to bleeding (two trials, 40,138 people). Of these 1,408 people, 884 (63%) died within the 12 hours after bleeding started.

In people with bleeding due to trauma or after giving birth, the chance of surviving any cause of death was 1.72 times higher in those who received tranexamic acid compared with those who received a placebo (odds ratio [OR] 1.72, 95% confidence interval [CI] 1.42-2.10, p<0.001).

Tranexamic acid also increased overall survival from bleeding (OR 1.20, 95% CI 1.08 to 1.33).In the tranexamic group deaths due to bleeding (3.2%) were less than in the placebo group (3.8%). This difference of 0.6% suggests that at least six deaths from bleeding complications in every 1,000 people treated with this drug could be prevented.

The survival benefits of tranexamic acid were estimated to decrease by 10% with every 15-minute delay in treatment.

There didn’t appear to be an improvement in survival when tranexamic acid was given 180 minutes after bleeding started.

What does current guidance say on this issue?

NICE 2016 guidelines recommend intravenous tranexamic acid as soon as possible in people with major trauma and active or suspected active bleeding. They do not recommend intravenous tranexamic acid more than three hours after injury in patients with major trauma unless there is evidence of hyperfibrinolysis (increased activity of the processes in the body that stop blood from clotting).

NICE 2017 guidelines recommend tranexamic acid as an additional option for women with significant continuing postpartum haemorrhage (bleeding after giving birth) after first and second-line treatments.

What are the implications?

This review supports current guidance recommending tranexamic acid for people with bleeding after trauma or giving birth. It adds further data and analysis to suggest that trauma patients should be treated at the scene of injury and post-partum haemorrhage should be treated as soon as the diagnosis is made.

In women with bleeding after birth, tranexamic acid is currently recommended after giving other drugs first. There may be practical implications for setting emergency services up to revise their protocols for delivering this intervention if they have not already done so.

The findings from this review could contribute to efforts to ensure uptake of this lifesaving treatment, perhaps by use of audit, monitoring and feedback against the time of administration.

Why was this study needed?

In the UK over 16,000 people per year suffer major trauma, and it is the leading cause of death in those under 40 years old. Uncontrolled bleeding is a major contributor to death, and the estimated annual cost to the NHS of treating severe bleeding after trauma is over £148 million.

Between 2013 and 2015, 10 women in the UK died from bleeding after giving birth.

Evidence shows that tranexamic acid may reduce the risk of death in people with bleeding after trauma and in women who bleed after giving birth.

It is not yet clear to what extent this risk changes depending on treatment delay. The researchers wanted to find out what the evidence said about time to administration of tranexamic acid treatment in two clinical settings and to what extent delay beyond an hour affected survival.

What did this study do?

This meta-analysis included two randomised controlled trials involving 40,138 people with bleeding who received tranexamic acid or a placebo.

One trial (CRASH-2) included people with bleeding after trauma. The second (WOMAN) included women with bleeding after giving birth.

The researchers looked at the survival rates in active and placebo arms of these trials and analysed the link between this and the timing of tranexamic acid administration. It is not clear from the review what dose was given in each trial.

These trials were large and with over 40,000 patients recruited between them provide a precise estimate of this effect. Both trials included patients from developed and less-developed countries. The timing of original trauma in CRASH-2 was not always certain and so treatment delay time could have been underestimated but is unlikely to have changed the overall pattern of these findings.

What did it find?

A total of 3,558 people died, and 40% (1,408) died due to bleeding (two trials, 40,138 people). Of these 1,408 people, 884 (63%) died within the 12 hours after bleeding started.

In people with bleeding due to trauma or after giving birth, the chance of surviving any cause of death was 1.72 times higher in those who received tranexamic acid compared with those who received a placebo (odds ratio [OR] 1.72, 95% confidence interval [CI] 1.42-2.10, p<0.001).

Tranexamic acid also increased overall survival from bleeding (OR 1.20, 95% CI 1.08 to 1.33).In the tranexamic group deaths due to bleeding (3.2%) were less than in the placebo group (3.8%). This difference of 0.6% suggests that at least six deaths from bleeding complications in every 1,000 people treated with this drug could be prevented.

The survival benefits of tranexamic acid were estimated to decrease by 10% with every 15-minute delay in treatment.

There didn’t appear to be an improvement in survival when tranexamic acid was given 180 minutes after bleeding started.

What does current guidance say on this issue?

NICE 2016 guidelines recommend intravenous tranexamic acid as soon as possible in people with major trauma and active or suspected active bleeding. They do not recommend intravenous tranexamic acid more than three hours after injury in patients with major trauma unless there is evidence of hyperfibrinolysis (increased activity of the processes in the body that stop blood from clotting).

NICE 2017 guidelines recommend tranexamic acid as an additional option for women with significant continuing postpartum haemorrhage (bleeding after giving birth) after first and second-line treatments.

What are the implications?

This review supports current guidance recommending tranexamic acid for people with bleeding after trauma or giving birth. It adds further data and analysis to suggest that trauma patients should be treated at the scene of injury and post-partum haemorrhage should be treated as soon as the diagnosis is made.

In women with bleeding after birth, tranexamic acid is currently recommended after giving other drugs first. There may be practical implications for setting emergency services up to revise their protocols for delivering this intervention if they have not already done so.

The findings from this review could contribute to efforts to ensure uptake of this lifesaving treatment, perhaps by use of audit, monitoring and feedback against the time of administration.

Effect of treatment delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: a meta-analysis of individual patient-level data from 40 138 bleeding patients

BACKGROUND: Antifibrinolytics reduce death from bleeding in trauma and post-partum haemorrhage. We examined the effect of treatment delay on the effectiveness of antifibrinolytics.
METHODS: We did an individual patient-level data meta-analysis of randomised trials done with more than 1000 patients that assessed antifibrinolytics in acute severe bleeding. We identified trials done between Jan 1, 1946, and April 7, 2017, from MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, PubMed, Popline, and the WHO International Clinical Trials Registry Platform. The primary measure of treatment benefit was absence of death from bleeding. We examined the effect of treatment delay on treatment effectiveness using logistic regression models. We investigated the effect of measurement error (misclassification) in sensitivity analyses. This study is registered with PROSPERO, number 42016052155.
FINDINGS: We obtained data for 40 138 patients from two randomised trials of tranexamic acid in acute severe bleeding (traumatic and post-partum haemorrhage). Overall, there were 3558 deaths, of which 1408 (40%) were from bleeding. Most (884 [63%] of 1408) bleeding deaths occurred within 12 h of onset. Deaths from post-partum haemorrhage peaked 2-3 h after childbirth. Tranexamic acid significantly increased overall survival from bleeding (odds ratio [OR] 1.20, 95% CI 1.08-1.33; p=0.001), with no heterogeneity by site of bleeding (interaction p=0.7243). Treatment delay reduced the treatment benefit (p<0.0001). Immediate treatment improved survival by more than 70% (OR 1.72, 95% CI 1.42-2.10; p<0.0001). Thereafter, the survival benefit decreased by 10% for every 15 min of treatment delay until 3 h, after which there was no benefit. There was no increase in vascular occlusive events with tranexamic acid, with no heterogeneity by site of bleeding (p=0.5956). Treatment delay did not modify the effect of tranexamic acid on vascular occlusive events.
INTERPRETATION: Death from bleeding occurs soon after onset and even a short delay in treatment reduces the benefit of tranexamic acid administration. Patients must be treated immediately. Further research is needed to deepen our understanding of the mechanism of action of tranexamic acid.
FUNDING: UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation (CRASH-2 trial). London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation (WOMAN trial).

Expert commentary

The two large randomised trials in this meta-analysis have already changed clinical practice in the UK NHS, and in many other countries around the world. The use of antifibrinolytics has been widely incorporated into guidelines for managing patients with acute haemorrhage in many settings.

What this paper adds is clear evidence that the timing of the administration of the antifibrinolytics is important; the earlier the administration, the greater the reduction in blood loss.

The new challenge for healthcare professionals is to create systems and pathways which facilitate the early administration of antifibrinolytics, preferably at the scene of the haemorrhage. This is no easy task. Pre-hospital and emergency department staff is already under huge pressure. However, the potential benefits for patients are enormous.